Compounds and medical devices activated with solvophobic linkers

ABSTRACT

The present disclosure relates to compounds and medical devices activated with a solvophobic material functionalized with a first reactive member and methods of making such compounds and devices.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.14/612,353 filed Feb. 3, 2015, which is a divisional of U.S. patentapplication Ser. No. 13/202,366 filed Oct. 13, 2011, now U.S. Pat. No.8,969,473, which is a National Stage Application of PCT/IB10/000630filed Feb. 22, 2010, which claims the benefit of and priority to U.S.Provisional Application No. 61/154,374 filed Feb. 21, 2009, and thedisclosures of each of the above-identified applications are herebyincorporated by reference in their entirety.

BACKGROUND Technical Field

The present disclosure relates to functionalized compounds havingsolvophilic and solvophobic portions and to activated medical devicesmade with such compounds.

Background of Related Art

The systemic administration of bioactive agents, such as by intravenousmeans, treats the body as a whole even though the disease to be treatedis often localized. Thus, efforts have recently been made to developmedical devices having a bioactive agent bound to the medical devices,to deliver the bioactive agent directly to the area of localization whenthe medical device in implanted. However, the development of suchmedical devices is highly complex and is often limited in practice bynumber of practical reactions available to combine the medical devicewith the agents, as well as the resultant by-products of the device upondegradation of the device in the body.

Accordingly, it would be beneficial to provide a compound or medicaldevice which does not require any complex reaction schemes orcross-linking reactions but rather requires the simple combination orblending of ingredients to produce an activated compound or medicaldevice capable of easily attaching to a bioactive agent.

SUMMARY

Compounds described herein include a solvophilic portion and asolvophobic portion where the solvophobic portion is functionalized withone or more first reactive members.

By “reactive member” is meant, according to the present application anyreactive member of functional group capable of interacting with anotherreactive member, in other words a complementary reactive member, inorder to form covalent bonds. In the present application, the terms“reactive member”, functional group” are used interchangeably. In thepresent application, the first reactive member and the second reactivemember are able to interact with one another form covalent bonds.

The first reactive members of the activated compounds may provide forthe covalent attachment of a variety of materials, such as, for example,bioactive agents functionalized with reactive members, also calledsecond reactive members, that are complementary to the first reactivemembers.

Medical devices containing such activated compounds are also describedherein. By “activated” or “functionalized” compound or medical device,is meant, according to the present application, a compound or medicaldevice functionalized by, in other words with, a reactive member. Themedical devices combine an activated compound with a solvent matrix. Theactivated compound includes a solvophilic portion that is relativelycompatible with the solvent matrix and a solvophobic portion that isrelatively incompatible with the solvent matrix and therefore remains ator near the surface of the device. Because the solvophobic portion isfunctionalized with a first reactive member, the reactive member is alsopositioned at or near the surface of the solvent matrix, therebycreating a medical device having an activated surface.

-   -   Methods for forming such compounds and devices are also        described.

A first aspect of the invention is a compound comprising:

-   -   a solvophilic material and a solvophobic material, the        solvophobic material being functionalized with a first reactive        member.

Another aspect of the invention is a method of forming an activatedmedical device comprising:

-   -   preparing a composition by combining a solvent matrix with a        compound which includes a solvophilic material and a solvophobic        material, the solvophobic material being functionalized with a        first reactive member, and    -   forming at least a portion of a medical device from the        composition.

Another aspect of the invention is a medical device comprising

-   -   a solvent matrix and a compound including a solvophobic material        and a solvophilic material, the solvophobic material being        functionalized with a first reactive member,    -   wherein the solvophilic material is positioned within the        solvent matrix and the solvophobic material including the        reactive member is positioned outside the solvent matrix.

In embodiments, the first reactive member is an electrophilic group. Inalternative embodiments, the first reactive member is a nucleophilicgroup. In alternative embodiments, the first reactive member is analkyne group. In alternative embodiments, the first reactive member isan azide group.

In embodiments, the solvent matrix is selected from the group consistingin a solid, a gel and a liquid.

In embodiments, the solvent matrix is hydrophilic. In such embodiments,the solvophilic material may include polyamides, hydrophilicpolyurethanes, polylactones, polyimides, polylactams,poly-vinyl-pyrrolidone, polyvinyl alcohols, polyacrylic acid,polymethacrylic acid, poly(hydroxyethyl methacrylate), gelatin, dextan,oligosaccharides, such as chitosan, hyaluronic acid, alginate,chondroitin, mixtures and combinations thereof. The solvophobic materialmay therefore include polyethylene, polypropylene, hydrophobicpolyurethanes, polyacrylates, polymethacrylates, fluoropolymers,polycaprolactone, polylactide, polyglycolide, phospholipids, andpolyureas, poly(ethylene/-vinyl acetate), polyvinylchloride, polyesters,polyamides, polycarbonate, polystyrenes, polytetrafluoroethylene,silicones, siloxanes, fatty acids, and chitosan having high degrees ofacetylation and mixtures and combinations thereof.

In embodiments, the medical device further comprises a bioactive agentfunctionalized with a second reactive member, said bioactive agent beingcovalently bound to said solvophobic material by means of said firstreactive member covalently bonding with said second reactive member.

For example, when the first reactive member is an alkyne group, thesecond reactive member may be an azide group.

Alternatively, when the first reactive member is an azide group, thesecond reactive member may be an alkyne group. In another embodiment,the first reactive member is an azide group and the second reactivemember is an alkene group.

In alternative embodiments, the first reactive member is anelectrophilic group and the second reactive member is a nucleophilicgroup. Alternatively, when the first reactive member is a nucleophilicgroup, the second reactive member may be an electrophilic group.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates an embodiment described herein of anactivated compound;

FIG. 2 schematically illustrates embodiments described herein of anactivated medical device; and

FIGS. 3 and 4 schematically illustrate the formation of a medical devicein accordance with the present disclosure.

FIG. 5 is a schematic illustration of an apparatus which is suitable forcarrying out a fiber manufacturing process in accordance with thepresent disclosure;

FIGS. 6 and 7 schematically illustrate apparatus suitable for carryingout an alternate fiber manufacturing process in accordance with thepresent disclosure; and

FIG. 8 schematically illustrate another apparatus suitable for carryingout a fiber manufacturing process in accordance with the presentdisclosure.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As shown in FIG. 1 and in accordance with the present disclosure,activated compound 10 includes solvophilic portion 20 and solvophobicportion 30 wherein solvophobic portion 30 is functionalized with firstreactive member 40. Solvophobic portion 30 and solvophilic portion 20are covalently bonded to one another. First reactive member 40 providesa site for attachment of another compound (not shown in FIG. 1), suchas, for example, a bioactive agent functionalized with a second reactivemember which is complementary to the first reactive member of theactivated compound.

The activated compounds may be combined with a solvent matrix to formactivated implantable medical devices. The medical devices describedherein include a solvent matrix and an activated compound which includesa solvophilic portion and a solvophobic portion. When combined, thesolvophilic portion of the activated compound is positioned within thesolvent matrix and at least a portion of the solvophobic portion, whichis functionalized with a first reactive member, is positioned outside,at or near the surface of the solvent matrix.

Turning now to FIG. 2, medical device 150, shown as a single fiber ormonofilament 115, includes solvent matrix 160 and activated compound 110which includes solvophilic portion 120 and solvophobic portion 130 withsolvophobic portion 130 being functionalized with first reactive member140. Solvophilic portion 120 is positioned closer in proximity tosolvent matrix 160 than solvophobic portion 130. Solvophobic portion130, which is not attracted to and relatively incompatible with solventmatrix 160, is positioned outside or at the surface of solvent matrix160, along with first reactive member 140.

As shown in FIG. 3, medical device 250 includes solvent matrix 260 andactivated compound 210. Activated compound 210 includes first reactivemember 240 (in this illustrative example an azide group) positioned onsolvophobic portion 230 and solvophilic portion 220 which, due to itscompatibility with solvent matrix 260, remains substantially withinsolvent matrix 260. A compound 270 to be covalently bound to device 250includes bioactive agent 280 that is functionalized with second reactivemember 290. Second reactive member 290 (in this illustrative example analkyne group) is complementary to first reactive member 240.

As shown in FIG. 4, bioactive agent 280 is covalently attached tomedical device 210 via linkage 295 following the interaction between thefirst reactive member positioned on the solvophobic portion of theactivated compound and the second reactive member on the bioactiveagent. In this illustrative example, where the first reactive member isan azide and the second reactive member is alkyne, linkage 295 is atriazole structure.

The Solvent Matrix

The solvent matrix is any material that can form a portion of a medicaldevice. For example, the solvent matrix may form the entire device, aportion of the device, a coating on the device or may be containedwithin a reservoir of the device. In embodiments, the solvent matrix isa solid. In other embodiments, the solvent matrix is a gel.

It is also contemplated that the solvent matrix could, at the time ofincorporation of the activated compound, be a liquid. Thus, for example,in embodiments the solvent matrix may be a solution of a polymer at thetime the activated compound is incorporated therein. Due to the mobilenature of the activated compound in the solution, the solvophobicportion of the activated compound migrates to the surface of thesolution. Upon evaporation of the solvent, a solid polymer remainshaving the solvophobic portion at or outside the surface of the solid.

In other embodiments, the solvent matrix can be a melt of one or morepolymers into which the activated compound is added. Due to the reducedviscosity of the melt, the solvophobic portion of the activated compoundwill migrate to the surface of the melt. Upon cooling, the solvophobicportion will be locked at or near the surface of the solidified polymercomposition.

In embodiments, the solvent matrix of the medical devices describedherein may include any biodegradable polymer. The biodegradable polymermay be a homopolymer or a copolymer, including random copolymer, blockcopolymer, or graft copolymer. The biodegradable polymer may be a linearpolymer, a branched polymer, or a dendrimer. The biodegradable polymersmay be of natural or synthetic origin. Examples of suitablebiodegradable polymers include, but are not limited to polymers such asthose made from lactide, glycolide, caprolactone, valerolactone,carbonates (e.g., trimethylene carbonate, tetramethylene carbonate, andthe like), dioxanones (e.g., 1,4-dioxanone), δ-valerolactone,1,dioxepanones (e.g., 1,4-dioxepan-2-one and 1,5-dioxepan-2-one),ethylene glycol, ethylene oxide, esteramides, γ-hydroxyvalerate,β-hydroxypropionate, alpha-hydroxy acid, hydroxybuterates, poly (orthoesters), hydroxy alkanoates, tyrosine carbonates, polyimide carbonates,polyimino carbonates such as poly (bisphenol A-iminocarbonate) and poly(hydroquinone-iminocarbonate), polyurethanes, polyanhydrides, polymerdrugs (e.g., polydiflunisol, polyaspirin, and protein therapeutics) andcopolymers and combinations thereof. Suitable natural biodegradablepolymers include those made from collagen, chitin, chitosan, cellulose,poly (amino acids), polysaccharides, hyaluronic acid, gut, copolymersand derivatives and combinations thereof.

Suitable non-biodegradable materials which may be used as part of thesolvent matrix include fluorinated polymers (e.g., fluoroethylenes,propylenes, fluoroPEGs), polyolefins such as polyethylene, polyesterssuch as poly ethylene terepththalate (PET), nylons, polyamides,polyurethanes, silicones, ultra high molecular weight polyethylene(UHMWPE), polybutesters, polyaryletherketone, copolymers andcombinations thereof.

Additionally, non-biodegradable polymers and monomers may be combinedwith each other and may also be combined with various biodegradablepolymers and monomers to create a solvent matrix.

As noted above, at the time of incorporation of the activated compound,the solvent matrix may take the form of any solution, suspension,semi-solid, or solid material capable of allowing the two components tobe combined and for the activated compound to migrate toward the surfaceof the solvent matrix. Thus, in embodiments, the solvent matrix may, inaddition to the polymers identified above, may include one or moresolvents. Suitable solvents include any solvent capable of dissolving orsuspending the polymer used. Suitable solvents which may be utilizedinclude, for example, polar solvents such as water, ethanol, triethyleneglycol, dimethyl sulfoxide, glymes (such as diglyme, triglyme,tetraglyme, and the like), polyethylene glycols, methoxy-polyethyleneglycols, dimethylformamide, dimethylacetamide, gamma-butyrolactone,n-methylpyrollidone, ketones such as methyl ethyl ketone, cyclohexanone,diethylene glycol momethyl ether acetate, diethylene glycol monobutylether acetate, diethylene glycol monomethyl ether, diethylene glycolmonoethyl ether, diethylene glycol monobutyl ether, diethylene glycolmonoisobutyl either, diisobutyl ketone, diacetone alcohol, ethyl amylketone, ethyl lactate, and the like. In other embodiments, solvents suchas tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate,isopropanol, butanol, acetone, and the like, may be utilized. Inembodiments, combinations of any of the foregoing solvents may beutilized to disperse or dissolve the polymer(s). The amount of solventused will depend on a number of factors, including the particularpolymer or combination of polymers to be employed and the intended enduse of the composition.

Other suitable non-limiting solvents include aromatic hydrocarbons, suchas toluene, petroleum naphtha or xylenes; nitro paraffins, such as1-nitropropane and 2-nitropropane, ketones such as, methyl amyl ketone,methyl isobutyl ketone, methyl ethyl ketone or acetone; esters such as,butyl acetate or hexyl acetate; and glycol ether esters C₁ to C₁₂ monoand di-alcohols, such as, for example, isopropanol, ethanol, methanol,butanol, isobutanol, acetone, diacetone alcohol, 2-ethylhexanol anddodecanol; tetrahydrofuran, glycol ethers and glycol ether acetates suchas, propylene glycol monomethyl ether acetate; toluene; benzene; xylene;chlorinated aliphatic solvents; hexane; butyl cellosolve; butylcellosolve acetate; methyl amyl alcohol, cyclohexanone, primary amylacetate, methyl amyl ketone, 2-ethyl hexanol, propanol, ethyl acetate,tetrahydrofuran, isopropyl acetate, 2-ethyl hexyl acetate, ethyl3-ethoxy propionate, pentyl propionate, ethanol, n-butyl propionate,tertiary butyl alcohol and 1-pentanol and carbitol.

The Activated Compounds

The activated compounds include at least one portion which issolvophilic and at least one portion which is solvophobic. The term“solvophilic” is generally defined in terms of being miscible,compatible, or attracted to, a given solvent matrix. The term“solvophobic” is generally defined in terms of being immiscible,incompatible, or not attracted to a given solvent matrix. As describedbelow, a variety of different solvent matrix materials may be combinedwith the activated compounds to form the medical devices describedherein, thus a given material may be either solvophobic or solvophilicdepending upon the solvent matrix. The activated compounds may belinear, branched, block or graft copolymers.

As noted above, in embodiments the solvent matrix can simply be a moltenpolymer or combination of polymers. In such embodiments, the activatedcompound may include a solvophilic portion that is an oligomer of themolten polymer. The solvophobic portion of the compound would beselected from materials that are immiscible, incompatible, or notattracted to the molten polymer(s).

In embodiments wherein the solvent matrix is hydrophilic in nature, thesolvophilic portions may be derived from hydrophilic polymers orcompounds. Suitable hydrophilic materials which may make up thesolvophilic portion of the compound include polyamides, hydrophilicpolyurethanes, polylactones, polyimides, polylactams,poly-vinyl-pyrrolidone, polyvinyl alcohols, polyacrylic acid,polymethacrylic acid, poly(hydroxyethyl methacrylate), gelatin, dextan,oligosaccharides, such as chitosan, hyaluronic acid, alginate,chondroitin, mixtures and combinations thereof. In such embodiments, thesolvophobic materials may be derived from hydrophobic polymers orcompounds selected from the group consisting of polyethylene,polypropylene, hydrophobic polyurethanes, polyacrylates,polymethacrylates, fluoropolymers, polycaprolactone, polylactide,polyglycolide, phospholipids, and polyureas, poly(ethylene/-vinylacetate), polyvinylchloride, polyesters, polyamides, polycarbonate,polystyrenes, polytetrafluoroethylene, silicones, siloxanes, fattyacids, and chitosan having high degrees of acetylation and mixtures andcombinations thereof. The activated compounds may include anybiocompatible combination of solvophilic and solvophobic materials.

In embodiments, the activated compound may include a solvophobicmaterial derived from a fatty acid, some non-limiting examples includesaturated fatty acids, monoenoic fatty acids, polyenoic fatty acids,methylene-interrupted polymethylene-interrupted, conjugated, allenicacids, cumulenic acids, acetylenic fatty acids, hydroxy fatty acids,dicarboxylic acids, fatty acid carbonates, divinyl ether fatty acids,sulfur containing fatty acids, fatty acid amides, methoxy and acetoxyfatty acids, keto fatty acids, aldehydic fatty acids, halogenated fattyacids (F, Cl, Br), nitrated fatty acids, arsenic containing fatty acids,branched-chain fatty acids, mono or multibranched chain fatty acids,branched methoxy fatty acids, branched hydroxy fatty acids, ringcontaining fatty acids, cyclopropane acids, cyclobutane acids,cyclopentenyl acids, furanoid acids, cyclohexyl acids, phenylalkanoicacids, epoxy acids, cyclic fatty peroxides, lipoic acids andcombinations thereof. Examples of saturated fatty acids includebutanoic, pentanoic, hexanoic, octanoic, nonanoic, decanoic, dodecanoic,tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, eicosanoic,docosanoic, tetracosanoic, hexacosanoic, heptacosanoic, andoctacosanoic. In embodiments, the fatty acid may include one of thefollowing formulas: C₆H₁₁O, C₁₀H₁₉O, C₁₆H₃₁O, C₂₂H₄₃O. The activatedcompound may also includes a solvophilic material derived from anoligosaccharide such as chitosan, hyaluronic acid, alginates orchondroitin sulfate.

Chitosan is a natural polysaccharide comprising copolymers ofglucosamine and N-acetylglucosamine, and can be obtained by the partialacetylation of chitin, from crustacean shells, squid pen, and mushroomsthe second most abundant natural polymer after cellulose. The process ofacetylation involves the removal of acetyl groups from the molecularchain of chitin, leaving behind a complete amino group (—NH₂) andchitosan versatility depends mainly on this high degree chemicalreactive amino groups. As the degree of acetylation increases, the morehydrophobic the chitosan becomes. Conversely, as the degree ofacetylation decreases, the more hydrophilic the chitosan becomes atpH<6. Thus, in some embodiments, chitosan oligmers displaying differentdegrees of acetylation (and hence different degrees of solvophilicityand solvophobicity) may be combined to form an activated compound.Moreover, in some embodiments in which more than one oligosaccharide maybe utilized to form the activated compound, the degree of acetylation ofthe chitosan oligomers may be altered depending on the solvophilicity ofthe other oligosaccharides. For instance, the activated compound mayinclude a solvophilic portion derived from a chitosan oligomer having alow degree of acetylation, ranging from about 0 to about 30%, and asolvophobic portion derived from a chitosan oligomer having a higherdegree of acetylation, greater than about 50% at a pH<6. Alternatively,the activated compound may be formed under a raised pH (pH>7) such thatthe compound includes a solvophobic portion derived from a chitosanoligomer having a low degree of acetylation, ranging from about 0 toabout 10%, and a solvophilic portion derived from a hyaluronic acidoligomer or alginate oligomer which under the raised pH conditionsdisplays a negative charge. Under the raised pH conditions, the chitosanoligomer having a low degree of acetyltion displays a positive chargeand becomes more solvophilic.

In still other embodiments, a fatty acid solvophobic portion may becombined with a solvophilic peptide or drug. Some non-limiting examplesof solvophilic polypeptides or drugs include oxytocin, vasopressin,adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF),transforming growth factor antagonists, prolactin, luliberin orluteinizing hormone releasing hormone (LH-RH), LH-RH agonists orantagonists, growth hormone, growth hormone releasing factor, insulin,somatostatin, bombesin antagonists, glucagon, interferon, gastrin,tetragastrin, pentagastrin, urogastrone, secretin, calcitonin,enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins,polymyzins, colistins, tyrocidin, gramicidines, and synthetic analoguesand modifications and pharmaceutically-active fragments thereof,monoclonal antibodies and soluble vaccines.

Where the solvent matrix is in the form of a solution, suspension oremulsion of a polymer, the solvophilic portion of the compound may bechosen to be miscible, compatible, or attracted to, a the solvent usedto make the solution, suspension or emulsion and the solvophobic portionof the compound may be chosen to be immiscible, incompatible, or notattracted to a given solvent used to make the solution, suspension oremulsion. For a given solvent matrix, those skilled in the art readingthe present disclosure will readily envision suitable solvophilic andsolvophobic materials to form the activated compound.

The solvophilic and solvophobic portions of the compound are covalentlybound together using techniques within the purview of those skilled inthe art.

Functionalizing the Solvophobic Portion of the Compound

In order to activate the compound, the solvophobic portion of thecompound is functionalized with a first reactive member. In order tocovalently bond another compound (e.g., a bioactive agent) to thesolvophobic portion of the activated compound, the solvophobic portionof the activated compound is functionalized with a first reactive memberand the other compound is functionalized with a second reactive memberthat is complementary to the first reactive members. By “complementary”it is meant that the first and second reactive members are able tointeract with one another to covalently bond the bioactive agent to theactivated compound.

In embodiments, the solvophobic portion of the compound isfunctionalized with electrophilic or nucleophilic functional groups,such that, for example, a nucleophilic functional group on thesolvophobic portion of the activated compound may later be reacted withan electrophilic functional group on another compound (e.g., a differentactivated compound containing a bioactive agent) to form a covalentbond.

Virtually any nucleophilic group can be used to functionalize thesolvophobic portion of the compound. Alternatively, virtually anyelectrophilic group can be used to functionalize the solvophobic portionto create the activated compound. In embodiments, the reaction occurswithout need for ultraviolet or other radiation. In embodiments, thereactions the complementary groups should be complete in under 60minutes, in embodiments under 30 minutes, in yet other embodiments, thereaction occurs in about 5 to 15 minutes or less.

Non-limiting examples of nucleophilic groups include, but are notlimited to, —NH₂, —NHR, —N(R)₂, —SH, —OH, —COOH, —C₆H₄—OH, —PH₂, —PHR,—P(R)₂, —NH—NH₂, —CO—NH—NH₂, —C₅H₄N, etc. wherein R is hydrocarbyl,typically C₁-C₄ alkyl or monocyclic aryl. Organometallic moieties arealso useful nucleophilic groups for the purposes of this disclosure,particularly those that act as carbanion donors. Examples oforganometallic moieties include: Grignard functionalities -RMgHalwherein R is a carbon atom (substituted or unsubstituted), and Hal ishalo, typically bromo, iodo or chloro; and lithium-containingfunctionalities, typically alkyllithium groups; sodium-containingfunctionalities.

It will be appreciated by those of ordinary skill in the art thatcertain nucleophilic groups must be activated with a base so as to becapable of reaction with an electrophile. For example, when there arenucleophilic sulfhydryl and hydroxyl groups on the solvophobic materialof the activated compound or activated medical device, the bioactiveagent must be admixed with an aqueous base in order to remove a protonand provide an —S⁻ or —O⁻ species to enable reaction with anelectrophile. Unless it is desirable for the base to participate in thereaction, a non-nucleophilic base is used. In some embodiments, the basemay be present as a component of a buffer solution.

The selection of electrophilic groups provided on the compound to becovalently bound to the activated compound is made so that reaction ispossible with the specific nucleophilic groups on the solvophobicportion of the activated compound. Thus, when the solvophobic portion ofthe activated compound is functionalized with amino groups, the compoundto be covalently bound to the activated compound is functionalized withgroups selected so as to react with amino groups. Analogously, when thesolvophobic portion of the activated compound is functionalized withsulhydryl moieties, the corresponding electrophilic groups can besulfhydryl-reactive members, and the like.

In embodiments, when the solvophobic portion of the activated compoundis functionalized with amino groups (generally although not necessarilyprimary amino groups), the electrophilic groups present on the compoundto be covalently bound to the activated compound are amino reactivemembers such as, but not limited to: (1) carboxylic acid esters,including cyclic esters and “activated” esters; (2) acid chloride groups(—CO—Cl); (3) anhydrides (—(CO)—O—(CO)—R); (4) ketones and aldehydes,including α,β-unsaturated aldehydes and ketones such as —CH═CH—CH═O and—CH═CH—C(CH₃)═O; (5) halides; (6) isocyanate (—N═C═O); (7)isothiocyanate (—N═C═S); (8) epoxides; (9) activated hydroxyl groups(e.g., activated with conventional activating agents such ascarbonyldiimidazole or sulfonyl chloride); and (10) olefins, includingconjugated olefins, such as ethenesulfonyl (—SO₂CH═CH₂) and analogousfunctional groups, including acrylate (—CO₂—C═CH₂), methacrylate(—CO₂—C(CH₃)═CH₂)), ethyl acrylate (—CO₂—C(CH₂CH₃)═CH₂), andethyleneimino (—CH—CH—C═NH). Since a carboxylic acid group per se is notsusceptible to reaction with a nucleophilic amine, components containingcarboxylic acid groups must be activated so as to be amine-reactive.Activation may be accomplished in a variety of ways, but often involvesreaction with a suitable hydroxyl-containing compound in the presence ofa dehydrating agent such as dicyclohexylcarbodiimide (DCC) ordicyclohexylurea (DHU). For example, a carboxylic acid can be reactedwith an alkoxy-substituted N-hydroxy-succinimide orN-hydroxysulfosuccinimide in the presence of DCC to form reactiveelectrophilic groups, the N-hydroxysuccinimide ester and theN-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may alsobe activated by reaction with an acyl halide such as an acyl chloride(e.g., acetyl chloride), to provide a reactive anhydride group. In afurther example, a carboxylic acid may be converted to an acid chloridegroup using, e.g., thionyl chloride or an acyl chloride capable of anexchange reaction. Specific reagents and procedures used to carry outsuch activation reactions will be known to those of ordinary skill inthe art and are described in the pertinent texts and literature.

Analogously, when the solvophobic portion of the activated compound isfunctionalized with sulfhydryl, the electrophilic groups present on thecompound to be covalently bound to the activated compound are groupsthat react with a sulfhydryl moiety. Such reactive members include thosethat form thioester linkages upon reaction with a sulfhydryl group, suchas mixed anhydrides; ester derivatives of phosphorus; ester derivativesof p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters ofsubstituted hydroxylamines, including N-hydroxyphthalimide esters,N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, andN-hydroxyglutarinide esters; esters of 1-hydroxybenzotriazole;3-hydroxy-3,4-dihydro-benzotriazin-4-one;3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives;acid chlorides; ketenes; and isocyanates. With these sulfhydryl reactivemembers, auxiliary reagents can also be used to facilitate bondformation, e.g., 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide can beused to facilitate coupling of sulthydryl groups to carboxyl-containinggroups.

In addition to the sulfhydryl reactive members that form thioesterlinkages, various other sulfydryl reactive functionalities can beutilized that form other types of linkages. For example, compounds thatcontain methyl imidate derivatives form imido-thioester linkages withsulfhydryl groups. Alternatively, sulthydryl reactive members can beemployed that form disulfide bonds with sulthydryl groups, such groupsgenerally have the structure —S—S—Ar where Ar is a substituted orunsubstituted nitrogen-containing heteroaromatic moiety or anon-heterocyclic aromatic group substituted with an electron-withdrawingmoiety, such that Ar may be, for example, 4-pyridinyl, o-nitrophenyl,m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic acid,2-nitro-4-pyridinyl, etc. In such instances, auxiliary reagents, i.e.,mild oxidizing agents such as hydrogen peroxide, can be used tofacilitate disulfide bond formation.

Yet another class of sulfhydryl reactive members forms thioether bondswith sulfhydryl groups. Such groups include, inter alfa, maleimido,substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as wellas olefins (including conjugated olefins) such as ethenesulfonyl,etheneimino, acrylate, methacrylate, and α,β-unsaturated aldehydes andketones.

When the solvophobic portion of the activated compound is functionalizedwith —OH, the electrophilic functional groups on the compound to becovalently bound to the activated compound are chosen to react withhydroxyl groups. The hydroxyl group may be activated as described abovewith respect to carboxylic acid groups, or it may react directly in thepresence of base with a sufficiently reactive electrophile such as anepoxide group, an aziridine group, an acyl halide, an anhydride,

When the solvophobic portion of the activated compound is functionalizedwith an organometallic nucleophile such as a Grignard functionality oran alkyllithium group, suitable electrophilic functional groups forreaction therewith are those containing carbonyl groups, including, byway of example, ketones and aldehydes.

It will also be appreciated that certain functional groups can react asnucleophiles or as electrophiles, depending on the selected reactionpartner and/or the reaction conditions. For example, a carboxylic acidgroup can act as a nucleophile in the presence of a fairly strong base,but generally acts as an electrophile allowing nucleophilic attack atthe carbonyl carbon and concomitant replacement of the hydroxyl groupwith the incoming nucleophile.

Table 1, below illustrates, solely by way of example, representativecomplementary pairs of electrophilic and nucleophilic functional groupsthat may be employed in functionalizing the solvophobic portion of theactivated compound (e.g., R₁ in Table 1) and the compound to becovalently bound to the activated compound (e.g., R₂ in Table 1).

TABLE 1 REPRESENTATIVE NUCLEOPHILIC REPRESENTATIVE COMPONENTELECTROPHILIC COMPONENT (A, FN_(Nu)) (B, FN_(EL)) RESULTING LINKAGER¹—NH₂ R²—O—(CO)—O—N(COCH₂) R¹—NH—(CO)—O—R² (succinimidyl carbonateterminus) R¹—SH R²—O—(CO)—O—N(COCH₂) R¹—S—(CO)—O—R² R¹—OHR²—O—(CO)—O—N(COCH₂) R¹—S—(CO)—R² R¹—NH₂ R²—O(CO)—CH═CH₂R¹—NH—CH₂CH₂—(CO)—O—R² (acrylate terminus) R¹—SH R²—O—(CO)—CH═CH₂R¹—S—CH₂CH₂—(CO)—O—R² R¹—OH R²—O—(CO)—CH═CH₂ R¹—O—CH₂CH₂—(CO)—O—R²R¹—NH₂ R²—O(CO)—(CH₂)₃—CO₂N(COCH₂) R¹—NH—(CO)—(CH₂)₃—(CO)—OR²(succinimidyl glutarate terminus) R¹—SH R²—O(CO)—(CH₂)₃—CO₂—N(COCH₂)R¹—S—(CO)—(CH₂)₃—(CO)—OR² R¹—OH R²—O(CO)—(CH₂)₃—CO₂—N(COCH₂)R¹—O—(CO)—(CH₂)₃—(CO)—OR² R¹—NH₂ R²—O—CH₂—CO₂—N(COCH₂)R¹—NH—(CO)—CH₂—OR² (succinimidyl acetate terminus) R¹—SHR²—O—CH₂—CO₂—N(COCH₂) R¹—S—(CO)—CH₂—OR² R¹—OH R²—O—CH₂—CO₂—N(COCH₂)R¹—O—(CO)—CH₂—OR² R¹—NH₂ R²—O—NH(CO)—(CH₂)₂—CO₂—N(COCH₂)R¹—NH—(CO)—(CH₂)₂—(CO)—NH—OR² (succinimidyl succinamide terminus) R¹—SHR²—O—NH(CO)—(CH₂)₂—CO₂—N(COCH₂) R¹—S—(CO)—(CH₂)₂—(CO)—NH—OR² R¹—OHR²—O—NH(CO)—(CH₂)₂—CO₂—N(COCH₂) R¹—O—(CO)—(CH₂)₂—(CO)—NH—OR² R¹—NH₂R²—O—(CH₂)₂—CHO R¹—NH—(CO)—(CH₂)₂—OR² (propionaldehyde terminus) R¹—NH₂

R¹—NH—CH₂—CH(OH)—CH₂—OR² and R¹—N[CH₂—CH(OH)—CH₂—OR²]₂ R¹—NH₂R²—O—(CH₂)₂—N═C═O R¹—NH—(CO)—NH—CH₂—OR² (isocyanate terminus) R¹—NH₂R²—SO₂—CH═CH₂ R¹—NH—CH₂CH₂—SO₂—R² (vinyl sulfone terminus) R¹—SHR²—SO₂—CH═CH₂ R¹—S—CH₂CH₂—SO₂—R²

In embodiments, the solvophobic portion of the compound isfunctionalized with a first click-reactive member and the compound to beattached thereto is functionalized with a second click-reactive membercomplementary to the first click-reactive member. The “click-reactivemembers” are meant to include those reactive members used in theprocesses known to those skilled in the art as Click chemistry.

Click chemistry refers to a collection of reactive members having a highchemical potential energy capable of producing highly selective, highyield reactions. The reactive members react to form extremely reliablemolecular connections in most solvents, including physiologic fluids,and often do not interfere with other reagents and reactions. Examplesof click chemistry reactions include Huisgen cycloaddition, Diels-Alderreactions, thiol-alkene reactions, and maleimide-thiol reactions.

Huisgen cycloaddition is the reaction of a dipolarophile with a1,3-dipolar compound that leads to 5-membered (hetero)cycles. Examplesof dipolarophiles are alkenes and alkynes and molecules that possessrelated heteroatom functional groups (such as carbonyls and nitriles).1,3-Dipolar compounds contain one or more heteroatoms and can bedescribed as having at least one mesomeric structure that represents acharged dipole. They include nitril oxides, azides, and diazoalkanes.Metal catalyzed click chemistry is an extremely efficient variant of theHuisgen 1,3-dipolar cycloaddition reaction between alkyl-aryly-sulfonylazides, C—N triple bonds and C—C triple bonds which is well-suitedherein. The results of these reactions are 1,2 oxazoles, 1,2,3 triazolesor tetrazoles. For example, 1,2,3 triazoles are formed by a coppercatalyzed Huisgen reaction between alkynes and alkyl/aryl azides. Metalcatalyzed Huisgen reactions proceed at ambient temperature, are notsensitive to solvents, i.e., nonpolar, polar, semipolar, and are highlytolerant of functional groups. Non-metal Huisgen reactions (alsoreferred to as strain promoted cycloaddition) involving use of asubstituted cyclooctyne, which possesses ring strain andelectron-withdrawing substituents such as fluorine, that togetherpromote a [3+2] dipolar cycloaddition with azides are especiallywell-suited for use herein due to low toxicity as compared to the metalcatalyzed reactions. Examples include DIFO and DIMAC. Reaction of thealkynes and azides is very specific and essentially inert against thechemical environment of biological tissues. One reaction scheme may berepresented as:

where R and R′ are the activated compound and another compound (e.g., abioactive agent).

The Diels-Alder reaction combines a diene (a molecule with twoalternating double bonds) and a dienophile (an alkene) to make rings andbicyclic compounds. Examples include:

The thiol-alkene (thiol-ene) reaction is a hydrothiolation, i.e.,addition of RS—H across a C═C bond. The thiol-ene reaction proceeds viaa free-radical chain mechanism. Initiation occurs by radical formationupon UV excitation of a photoinitiator or the thiol itself. Thiol-enesystems form ground state charge transfer complexes and thereforephotopolymerize even in the absence of initiators in reasonablepolymerization times. However, the addition of UV light increases thespeed at which the reaction proceeds. The wavelength of the light can bemodulated as needed, depending upon the size and nature of theconstituents attached to the thiol or alkene. A general thiol-enecoupling reaction mechanism is represented below:

In embodiments, the solvophobic portion of the compound and a bioactiveagent are functionalized to include a first click-reactive member whichis an alkyne and a second click-reactive member which is an azide,respectively. In embodiments, the solvophobic portion of the compound ormedical device and the bioactive agent are functionalized to include afirst click-reactive member which is an azide and a secondclick-reactive member which is an alkyne, respectively. In yet otherembodiments, the solvophobic portion of the compound or medical deviceand the bioactive agent are functionalized to include a firstclick-reactive member which is an azide and a second click-reactivemember which is an alkene, respectively. See, van Berkel et al.CemBioChem, 8, pages 1504-1508 (2007).

The first and second click-reactive members are intended to react andcovalently bond the solvophobic portion of the activated compound to thefunctionalized bioactive agent at a physiologic pH. However, in someembodiments, the first and second click-reactive members may reactquicker or more completely following the addition of a catalyst, such asa pH modifier, a metal ion catalyst or the introduction of heat orradiation. In embodiments, the addition of UV radiation may enhance theformation of a covalent bond between the first and second click-reactivemembers, especially where those groups are a thiol group and an alkenegroup. In embodiments, the addition of a metal catalyst, e.g.,transition metal ions such as copper ions, may assist with the formationof a covalent bond between the first and second click-reactive members.

Bioactive Agents

The activated compounds may be covalently bonded to any of a variety ofcompounds functionalized with a second reactive member that iscomplementary to the first reactive member on the activated compound. Inembodiments, the compound functionalized with a second reactive memberis a bioactive agent functionalized with a second reactive member.Suitable bioactive agents include therapeutic, prophylactic ordiagnostic agents. A wide variety of bioactive agents can beincorporated, either for delivery to a site, or to impart properties tothe medical device, such as bioadhesion, cell attachment, enhancement ofcell growth, inhibition of bacterial growth, anti-adhesion, andprevention of clot formation.

Examples of suitable therapeutic and prophylactic agents includesynthetic inorganic and organic compounds, polymeric materials, proteinsand peptides, polysaccharides and other sugars, lipids, and DNA and RNAnucleic acid sequences having therapeutic, prophylactic or diagnosticactivities. Nucleic acid sequences include genes, antisense moleculeswhich bind to complementary DNA to inhibit transcription, and ribozymes.Compounds with a wide range of molecular weight can be encapsulated, forexample, between 100 and 500,000 grams or more per mole. Examples ofsuitable materials include proteins such as antibodies, receptorligands, and enzymes, peptides such as adhesion peptides, saccharidesand polysaccharides, synthetic organic or inorganic drugs such asantimicrobials, chemotherapeutics, anesthetics, and pain relievers.Other non-limiting examples include enzymes, blood clotting factors,inhibitors or clot dissolving agents such as streptokinase and tissueplasminogen activator; antigens for immunization; hormones and growthfactors; polysaccharides such as heparin; oligonucleotides such asantisense oligonucleotides and ribozymes; cellular materials; andretroviral vectors for use in gene therapy. Representative diagnosticagents are agents detectable by x-ray, fluorescence, magnetic resonanceimaging, radioactivity, ultrasound, computer tomagraphy (CT) andpositron emission tomagraphy (PET).

Functionalizing the Compound and the Agent

The first and second reactive members may be positioned on thesolvophobic portion of the compound and the compound to be attachedthereto (e.g., a bioactive agent) using any variety of suitable chemicalprocesses. With respect to the first and second reactive members on thesolvophobic portion and bioactive agents respectively, it iscontemplated that a plurality of first and second reactive members maybe present and may be terminally located, or alternatively located alongthe length of the any portion thereof.

For example, monomers from which the solvophobic portion is made can befunctionalized so that the reactive members appear along the length ofthe solvophobic portion. In such embodiments, the monomers can beinitially functionalized with a member such as a halogen to provide areactive site at which the desired first reactive member can be attachedafter polymerization. Thus, for example, a cyclic lactone (e.g.,glycolide, lactide, caprolactone, etc.) can be halogenated and thenpolymerized using known techniques for ring opening polymerization. Oncepolymerized, the halogenated sites along the resulting polyester chaincan be functionalized with the first reactive member. For example, thehalogenated polyester can be reacted with sodium azide to provide azidegroups along the polymer chain or with propagyl alcohol to providealkyne groups along the polymer chain. See, R. Riva et al., Polymer 49,pages 2023-2028 (2008) for a description of such reaction schemes. Inanother example, a propargyl group may be introduce into a cycliccarbonate monomer to form5-methyl-5-propargyloxycarbonyl-1,3-dioxan-2-one (MPC) which ispolymerizable with lactide to form p(LA-co-MPC). See, Q. Shi et al.,Biomaterials, 29, pages 1118-1126 (2008). Alternatively, a pre-formedbiodegradable polyester can be halogenated by reaction with anon-nucleophilic strong base, such as lithium diisopropylamide, followedby electrophilic substitution with iodine chloride. The halogenatedpolyester is then reacted with sodium azide or propagyl alcohol toprovide azide or alkyne groups, respectively. Other methods forfunctionalizing lactones are described in Jérôme et al., Advanced DrugDelivery Reviews, 60, pages 1056-1076 (2008). The entire disclosure ofeach of these articles is incorporated herein by this reference.

With respect to the solvophobic materials of the compound, it iscontemplated that one or more than one first reactive members can beprovided thereon. The process used to incorporate the first reactivemembers on the solvophobic material of the compound will be chosen basedupon the nature of the solvophobic portion.

For example, where the solvophobic portion is based on a fatty acid,reactive members can be attached using the following synthetic route:

In embodiments, the diacids may be used to introduce the acyl chains(10d) which will provide for the synthesis of di-azide compounds.

In other embodiments where the solvophobic portion is based on ahydrophobic peptide, N-propargyl maleimide can be used to attach alkynegroup (the second reactive members) on to the protein using to the thiolgroup as shown below:

In other embodiments where the solvophobic portion is based on ahydrophobic peptide azide groups may be provided by conversion of theamino acid methyl ester to the corresponding azide via aCu(II)-catalyzed diazotransfer reaction using triflic azide as shown inthe following reaction scheme:

In yet other embodiments where the solvophobic portion is based on anoligosaccharide, reactive members can be attached using the followingreaction scheme as described in detail in Zhang et al., HelveticaChimica Acta—Vol. 91 pages 608-617(2008):

In embodiments, a plurality of different reactive members may bepositioned on each of the solvophobic portion of the compound or medicaldevice and the compound to be covalently bound thereto.

The Medical Device

The medical devices described herein include the combination of asolvent matrix and an activated compound including a solvophobic portionand a solvophilic portion, the solvophobic portion being functionalizedwith a first reactive member, wherein the solvophilic portion ispositioned within the solvent matrix and the solvophobic portionincluding the reactive member is positioned outside, at or near thesurface of the solvent matrix.

The solvent matrix and the compound may be combined, mixed or blended,to form the activated medical devices described herein. The solvophobicmaterial of the compound will migrate to the outer portions of thesolvent matrix while the solvophilic materials will attempt to migrateto the center of the solvent matrix. Because the solvophilic andsolvophobic materials are covalently attached, varying degrees ofmigration are possible. In some embodiments, the solvophobic materialwill completely migrate outside the solvent matrix. In otherembodiments, only a portion of the solvophobic material will bepositioned outside the solvent matrix. The degree of migration will varyaccording to the materials chosen to form the compound and the solventmatrix.

The solvent matrix may represent from about 10% to about 99% of themedical device by weight. The solvent matrix may represent from about25% to about 95% of the medical device by weight.

The activated compound may represent from about 5 to about 90% of themedical device by weight.

The medical device may be formed into any desired physical form. Themedical device may include a solvent matrix which is polymeric andcreates a polymeric substrate. The medical device may be fabricated forexample, by extruding, melt processing, spinning, casting, molding,spray drying or any other fabrication technique known to those skilledin the art. The polymeric substrate may be made into any shape, such as,for example, a fiber, sheet, rod, staple, clip, needle, tube, foam, orany other configuration suitable for a medical device. Where thepolymeric substrate is in the form of a fiber, the fiber may be formedinto a textile using any known technique including, but not limited to,knitting, weaving, tatting and the like. It is further contemplated thatthe polymeric substrate may be a non-woven fibrous structure.

Any medical device suitable for implantation may be formed as describedherein. Some non-limiting examples include monofilaments,multifilaments, surgical meshes, ligatures, sutures, staples, patches,slings, foams, pellicles, films, barriers, and the like.

In embodiments, the solvent matrix includes one or more polymers thatcan combined with the activated compound and melt extruded into fibers.In an illustrative process, one or more polymers making up the solventmatrix and the activated compound may be placed in a hopper and mixedthoroughly to provide substantially uniform distribution of thecomponents. The components may be mixed using any conventionaltechnique, with or without heating. For example, a mechanical mixer, astatic mixer, or combinations thereof, may be employed to assist inproviding a substantially uniform distribution of the components. Aftermixing, the mixture is extruded or spun to form one or more filaments.

Known spinning apparatuses can be used for the production of filaments,in accordance with the present disclosure. FIG. 5 schematicallyillustrates a filament manufacturing operation in accordance with thedisclosure. Extruder unit 110 is of a known or conventional types and isequipped with controls for regulating the temperature of barrel 111 invarious zones thereof, e.g., progressively higher temperatures in threeconsecutive zones, A, B, and C along the length of the barrel. The firstand second precursors to be spun into filaments are introduced to theextruder through hopper 112. Prior to or during placement in hopper 112,the first precursor is combined with the second precursor and mixed in aone-pot process. Adding heat during the mixing and/or extruding stepsaids in the curing time of the first and second precursors, as fastercuring rates are observed at higher temperatures.

Motor-driven metering pump 113 delivers the melt extruded first andsecond precursor mixture at a constant rate and with high pressure tospin pack 114 and thereafter through spinneret 115 possessing one ormore orifices of desired diameter to provide a molten monofilament 116which then enters quench bath 117, e.g., containing water, where themonofilament solidifies. The distance monofilament 116 travels afteremerging from spinneret 115 to the point where it enters quench bath117, i.e., the air gap, can vary. If desired, a chimney (not shown), orshield, can be provided to isolate monofilament 116 from contact withair currents which might otherwise affect the cooling of themonofilament in an unpredictable manner. In general, barrel zone A ofthe extruder can be maintained at a temperature of from about 100° C. to220° C., zone B at from about 160° C. to 230° C. and zone C at fromabout 170° C. to about 240° C. Additional temperature parametersinclude: metering pump block 113 at from about 170° C. to about 230° C.,spin pack 114 at from about 170° C. to about 230° C., spinneret 115 atfrom about 170° C. to about 230° C. and quench bath at from about 10° C.to about 80° C.

Monofilament 116 is passed through quench bath 117 around driven roller118 and over idle roller 119. Optionally, a wiper (not shown) may removeexcess water from the monofilament as it is removed from quench bath117. On exiting the quench bath the monofilament is wrapped around afirst godet 121 provided with nip roll 122 to prevent slippage whichmight otherwise result from the subsequent stretching operation; andsubsequently wrapped around godets 101, 102, 103 and 104 or any othersuitable godet arrangement. Monofilament 116 passing from godet 104 isstretched, e.g., with stretch ratios on the order of from about 3:1 toabout 10:1 and preferably from about 4:1 to about 7:1, to effect itsorientation and thereby increase its tensile strength.

In the stretching operation, monofilament 116 may be drawn through hotwater (or other suitable liquid medium) draw bath 123 by means of godets124, 105, 106, 107 and 108 or any other suitable arrangement of godetswhich rotate at a higher speed than godet 104 to provide the desiredstretch ratio. The temperature of hot water draw bath 123 isadvantageously from about 30° C. to about 90° C. and preferably is fromabout 30° C. to about 50° C. In an alternative stretching operation,generally preferred for smaller sutures sizes, e.g., sizes 3/0 to 8/0,monofilament 116 may be drawn by godets 124, 105, 106, 107, and 108 orany other suitable godet arrangement through hot air convection ovenchamber 123 at a temperature of from about 30° C. to about 140° C., andpreferably from about 50° C. to about 130° C. to provide the desiredamount of stretch.

Following the stretching operation, monofilament 116 optionally may besubjected to an on-line annealing and/or additional stretching withoutshrinkage or relaxation with shrinkage operation as a result of whichthe monofilament shrinks. In the process of FIG. 1, on-line annealingwith or without relaxation when desired is accomplished by drivingmonofilament 116 by godets 126, 129, 130, 131, and 132 or any othersuitable godet arrangement through second hot air oven chamber 125 at atemperature of from about 40° C. to about 150° C., and preferably fromabout 60° C. to about 130° C. During the relaxation process, at thesetemperatures, monofilament 116 will generally recover to within about 80to about 97 percent, and preferably to within about 95 percent, of itspre-annealed length to provide the finished suture. For relaxation, thethird godet rotates at a slower speed than the second godet thusrelieving tension on the filament.

Annealing of the suture also may be accomplished without shrinkage ofthe suture. In carrying out the annealing operation, the desired lengthof suture may be wound around a creel and the creel placed in a heatingcabinet maintained at the desired temperature, e.g. about 60° C. toabout 130° C. After a suitable period of residency in the heatingcabinet, e.g., about 18 hours or so, the suture will have undergoneessentially no shrinkage. Variables such as the annealing temperatures,time, and pressure may affect the curing time of the fibers as well. Thecreel may be rotated within the heating cabinet in order to insureuniform heating of the monofilament or the cabinet may be of thecirculating hot air type in which case uniform heating of themonofilament will be achieved without the need to rotate the creel.Thereafter, the creel with its annealed suture is removed from theheating cabinet and when returned to room temperature, the suture isremoved from the creel, conveniently by cutting the wound monofilamentat opposite ends of the creel. The annealed sutures are then ready to bepackaged and sterilized.

In embodiments, fibers from chitin or chitin derivative combined with anactivated compound can be produced according to the present disclosureby spinning from anisotropic solution. Suitable methods for solutionspinning chitin or chitin derivative fibers in general are disclosed inEuropean Patent Nos. EP0328050A2 and EP0077098A2, the entire disclosuresof which are incorporated herein by this reference. Such fibers can havetensile properties which typically fall between 4-8 g/d tenacity and150-250 g/d initial modulus.

High strength chitosan fibers can be prepared by spinning an aniostropicsolution containing chitosan or a derivative of chitin or chitosan andan activated compound through an inert gas and into a coagulating bath,removing the as-spun fiber and treating it with alkali to removeN-acetyl, O-acetyl or other pendant groups at the 2, 3 and 6 carbonpositions of the glucosamine repeating unit. Treatment of fibers is byimmersion of the fibers into a solution of NaOH. With fine denierfibers, e.g., 4-5 dpf., a 5 minute immersion at 70° C. in a 50% wt.solution of NaOH is satisfactory. A 2-3 hr. exposure at 80° C. in a 30%wt. solution is useful with chitosan acetate formate fiber. Withchitosan acetate, temperatures in the range of 80° to 116° C. at NaOHconcentration of 30% have been found useful with the higher temperaturesrequiring less time for completion of the reaction. Severe treatmentsare generally to be avoided since they may cause excessive interfilamentfusion and a product of inferior quality. Conversion of the startingfiber to a chitosan fiber is confirmed if the chitosan fiber is readilysoluble in dilute (3-20% wt.) acetic acid.

In using the apparatus of FIG. 6 an anisotropic solution of chitin or achitin derivative is placed in spin cell (G). A piston (D) activated byhydraulic press (F) and associated with piston travel indicator (E) ispositioned over the surface of the solution, excess air is expelled fromthe top of the cell and the cell is sealed. The spin cell is fitted atthe bottom with the following screens (A) for solution filtration: fourto six 325-mesh screens. The filtered solution is then passed into aspinneret pack (B) containing two or three 325-mesh screens. Solutionsare extruded through an air gap at a controlled rate into a static bath(C) using a metering pump to supply pressure at piston (D). The fiber ispassed around a pin (H), pulled through the bath, passed under a secondpin (I) and wound onto a bobbin. The air gap between the spinneret faceand the coagulation bath is typically 0.6 to 2.0 cm. The coagulationbath temperature is generally held below 100° C.

In using the apparatus of FIG. 7, filter plate (J) is replaced by mixingplate (R). Polymer dope is placed in cylinder bore (T) and then piston(D) and cap plate (L) is fitted to the spin cell (G). A driver fluid(e.g. water) is pumped into the upper part of bore (T) through feed line(F). The piston (D) is displaced by the driver fluid, thereby pushingthe polymer dope through passages (W), (S) in mixing plate (R) and thenthrough passage (K) in distribution plate (M) into second cylinder bore(U). This process is then reversed by pumping fluid through feed line(X). The aforementioned forward and reverse process is repeated severaltimes to effect a mixing of the polymer dope. Component (E) acts tosense the position of cylinder (D).

After mixing is complete (about 30 cycles), mixing plate (R) is replacedby filter plate (J) and polymer dope is extruded from bore (T) throughpassage (W), through filter pack (A) containing 2 Dutch Twill Weave165×800 mesh screens, through passage (Y) in filter plate (J) andpassage (Z) in spinneret mounting plate (O) and out of spin cell (G)through spinneret (B). The extruded dope is spun into a bath and takenup as described for FIG. 2. Pressure of the polymer dope during spinningis measured by pressure transducer (P).

In other embodiments, fibers from collagen or collagen derivatives mixedwith an activated compound can be produced according to the presentdisclosure by gel spinning. Suitable methods for gel spinning collagenfibers in general are disclosed in U.S. Pat. Nos. 5,562,946 and5,911,942, the entire disclosures of which are incorporated herein bythis reference.

In an illustrative apparatus for gel spinning such fibers shown in FIG.8, collagen reservoir chamber 10 holds a liquid solution containingcollagen and the activated compound. In one embodiment, a suitablechamber is a stainless steel syringe. Reservoir tube 12 is attached tocollagen reservoir chamber 10 for directing collagen solution fromcollagen reservoir chamber 10 through infusion pump 14 to spinneret 16.Infusion pump 14 is capable of raising the pressure of the collagenmaterial such that it can be extruded through spinneret nozzle 17 ofspinneret 16. In embodiments, a positive displacement metering pump isused. Spinneret 16 can be single bore or multiple bore to producemonofilament or multifilament fibers respectively. The spinneret borescan be of various diameters or have tapered profiles to form fibers ofdifferent sizes and tensile strengths. Co-component fibers can beproduced with other specialized spinnerets as are known in the art. Inone embodiment, spinneret nozzle 17 has diameters in the range ofbetween about 100 and 1,000 microns.

Coagulation bath 18 has a coagulation solution 20 that can cause theliquid collagen to form a collagen gel, such as a 0.75% alkaline alginicacid in a boric acid buffer or sugar solutions or polyethylene glycolsolution which also has hydrophilic properties. The opening of spinneretis immersed in a flowing coagulation solution 20. Coagulation bath 18 issuitably sized for allowing extrusion of fiber from spinneret 16 throughcoagulation solution 20 while having a sufficient residency time forcollagen gel fiber 22 to form. Coagulation bath 18 can be heated andinstrumented for monitoring the relevant process variables, such astemperature, pH and velocity. Coagulation bath 18 allows collagen gelfiber 22 to be formed in a horizontal trough or in a tube or verticallyin a tube. Coagulation bath 18 is configured to allow circulation ofcoagulation solution 20 through recirculating loop 26 by circulatingpump 28. Coagulation bath flow can be in the same direction 30 of fibertravel. At the end of the coagulation bath 18, roller 32 is fordirecting fiber out of the coagulation bath. Roller 32 is motorized andcan be activated to wind collagen gel fiber 22 and subsequently towcollagen gel fiber 22 at desired speeds.

Dehydrating bath 34 is adjacent to roller 32 and coagulation bath 18 andis configured to allow fiber 22 to be drawn into dehydrating bath 34from roller 32. Dehydrating bath 34 holds dehydrating solution 36, suchas 90% ethanol, which allows further dehydration and annealing of thefiber and promotes polymerization of the collagen to improve fiberstrength. An example of another suitable dehydration solutioncomposition is acetone. Dehydrating bath 34 is configured to allowvariable circulation of dehydrating solution 36 through recirculatingloop 38 by circulating pump 40 which can be adjusted directionally, suchas direction 41 or in the opposite direction. Return rollers 42, whichcan be near each end of dehydrating bath 34, allow the fiber path to belengthened by doubling back to make any number of multiple passesthrough dehydrating bath 34 to allow further dehydration and promotepolymerization of the collagen.

Partially dehydrated fiber 44 is wound around roller 46 to second roller50 and then to stretching roller means 62, wherein the fiber can undergoa controlled deformation by being stretched between two groups ofrollers 64 rotating at slightly different rates of speed. The speed ofrotation of rollers 64 can be precisely controlled with digitalmicroprocessors arranged in a closed feedback loop. The fibers arewrapped around each roller 64 several times to prevent fiber slippagerelative to the roller surfaces. Roller 64 surfaces can made of apolymer or a hardened metal resistant to corrosion. Roller 64 rotationscan be adjusted individually to allow the fiber to be stretched beyondthe elastic yield point to produce a longer fiber of reduced diameter.Stretching roller means 62 can operate under semi-dry or dry conditionsand also under high moisture content atmosphere.

Drying cabinet 68 has opening 73 for receiving stretched fiber 70 fromstretching rollers 62. Drying cabinet 68 has passage 71 through dryingcabinet 68 for receiving warm, dry filtered air or a dry inert gas, suchas dry nitrogen gas, from gas source 72 at a suitable temperature andhumidity for drying stretched fiber 70. The air can be passed throughair passage opening 77 into passage 71 and exiting from air passageopening 79. In embodiments, the temperature of the air is between about35° C. and 39° C. The humidity is in the range of between 10 and 20percent relative humidity. Drying cabinet 68 has a series of rollers 74which allows stretched fiber 70 to remain in drying cabinet 68 whilebeing rolled, thereby increasing the residence time of fiber 70 indrying cabinet 68. Drying cabinet rollers 74 are adjustable in distancebetween each other and to compensate for the fiber line speed. Dryingcabinet rollers 74 can be driven at a surface roller speed that can besynchronized with that of stretching roller means 62. Drying cabinet 68has a door to provide access to the rollers for threading the leaderthread.

Take-up winder 76 is for receiving dried fiber 78 from exit 75 of dryingcabinet 68. Take-up winder 76 has spool 80 for receiving dried fiber ona removable spindle bobbin. Take-up winder 76 has a slip clutch 82 toprovide a constant fiber line tension and fiber line speed as thespooled fiber rotates radially around spool 80. Fiber spool 80 can windthe fiber level or by randomly winding with the take-up winder 76.

Fibers formed in accordance with the present invention may be used for avariety of surgical and wound applications. The fibers, for example, maybe used alone, such as for example, for closing wounds and incisions inthe form of monofilament or multifilament sutures. Multifilament suturesmay be constructed using any technique within the purview of thoseskilled in the art, such as spinning and braiding the fibers together.The fibers may also be used in combination with the other absorbable ornon-absorbable fibers to form multifilament sutures or to form knitted,woven, or non-woven meshes or fabrics. A wide variety of surgicalarticles can be manufactured from the fibers of the present disclosure.These include but are not limited to sutures as discussed above,threads, rods, filaments, yarns, meshes, slings, patches, wounddressings, drug delivery devices, fasteners, and other implants andcomposite materials, such as pledgets, buttresses, adhesion barriers,and the like.

Various modifications and variations of the polymers, amphiphiliccompounds, medical devices, click-reactive members and processesdescribed herein will be apparent to those skilled in the art from theforegoing detailed description. Such modifications and variations areintended to come within the scope of the following claims.

What is claimed is:
 1. An activated compound consisting of: asolvophilic material covalently bonded to a solvophobic material,wherein the solvophilic material is chitosan having a degree ofacetylation from about 0 to about 30% and the solvophobic material is afatty acid functionalized with a first click reactive member, the firstclick reactive member providing the activated compound with a site forfuture attachment of a bioactive agent via click chemistry.
 2. Thecompound of claim 1, wherein the first click reactive member is analkyne group.
 3. The compound of claim 1, wherein the first clickreactive member is an azide group.
 4. The compound of claim 1, whereinthe fatty acid is a saturated fatty acid selected from the groupconsisting of butanoic, pentanoic, hexanoic, octanoic, nonanoic,decanoic, dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic,octadecanoic, eicosanoic, docosanoic, tetracosanoic, hexacosanoic,heptacosanoic, and octacosanoic acids.
 5. A compound consisting of: asolvophilic material covalently bonded to a solvophobic material,wherein the solvophilic material is chitosan having a degree ofacetylation from about 0 to about 30% and the solvophobic material is afatty acid, and a bioactive agent covalently bonded to said solvophobicmaterial via click chemistry.
 6. The compound of claim 5, wherein thefatty acid is a saturated fatty acid selected from the group consistingof butanoic, pentanoic, hexanoic, octanoic, nonanoic, decanoic,dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic,eicosanoic, docosanoic, tetracosanoic, hexacosanoic, heptacosanoic, andoctacosanoic acids.
 7. The compound of claim 5, wherein the bioactiveagent is a therapeutic agent.
 8. The compound of claim 5, wherein thebioactive agent is a diagnostic agent.
 9. A compound consisting of asolvophilic material covalently bonded to a solvophobic material,wherein the solvophilic material is a hydrophilic peptide or drugcontaining a free amine and the solvophobic material is a fatty acid,and a bioactive agent covalently bonded to said solvophobic material viaclick chemistry.
 10. The compound of claim 9, wherein the fatty acid isa saturated fatty acid selected from the group consisting of butanoic,pentanoic, hexanoic, octanoic, nonanoic, decanoic, dodecanoic,tetradecanoic, hexadecanoic, heptadecanoic, octadecanoic, eicosanoic,docosanoic, tetracosanoic, hexacosanoic, heptacosanoic, and octacosanoicacids.
 11. The compound of claim 9, wherein the hydrophilic peptide ordrug is selected from the group consisting of oxytocin, vasopressin,adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF),transforming growth factor antagonists, prolactin, luliberin orluteinizing hormone releasing hormone (LH-RH), LH-RH agonists orantagonists, growth hormone, growth hormone releasing factor, insulin,somatostatin, bombesin antagonists, glucagon, interferon, gastrin,tetragastrin, pentagastrin, urogastrone, secretin, calcitonin,enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins,polymyzins, colistins, tyrocidin, gramicidines, and synthetic analoguesand modifications and pharmaceutically-active fragments thereof.
 12. Thecompound of claim 9, wherein the bioactive agent is a therapeutic agent.13. The compound of claim 9, wherein the bioactive agent is a diagnosticagent.
 14. A composition comprising: a hydrophilic solvent matrix; and asolvophilic material covalently bonded to a solvophobic material,wherein the solvophilic material is chitosan having a degree ofacetylation from about 0 to about 30% and the solvophobic material is afatty acid functionalized with a first click reactive member, the firstclick reactive member providing the activated compound with a site forfuture attachment of a bioactive agent via click chemistry.